Faculty Bibliography

OBJECTIVE:Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS:Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS:We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation, i.e., neurogenic OH, and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as non-neurogenic, due to volume depletion, anemia or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP) [-44±25 vs. -21±14 mmHg (mean±SD), p<0.0001] but only one third of the increase in HR than those with non-neurogenic OH (8±8 vs. 25±11 bpm, p<0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic vs. non-neurogenic OH (AUC=0.96, p<0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p=0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION/CONCLUSIONS:A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio lower than 0.5 bpm/mmHg is diagnostic of neurogenic OH.

BACKGROUND:Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS:We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS:A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION/CONCLUSIONS:Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Multiple system atrophy (MSA) may be difficult to distinguish clinically from other disorders, particularly in the early stages of the disease. An autonomic-only presentation can be indistinguishable from pure autonomic failure. Patients presenting with parkinsonism may be misdiagnosed as having Parkinson disease. Patients presenting with the cerebellar phenotype of MSA can mimic other adult-onset ataxias due to alcohol, chemotherapeutic agents, lead, lithium, and toluene, or vitamin E deficiency, as well as paraneoplastic, autoimmune, or genetic ataxias. A careful medical history and meticulous neurological examination remain the cornerstone for the accurate diagnosis of MSA. Ancillary investigations are helpful to support the diagnosis, rule out potential mimics, and define therapeutic strategies. This review summarizes diagnostic investigations useful in the differential diagnosis of patients with suspected MSA. Currently used techniques include structural and functional brain imaging, cardiac sympathetic imaging, cardiovascular autonomic testing, olfactory testing, sleep study, urological evaluation, and dysphagia and cognitive assessments. Despite advances in the diagnostic tools for MSA in recent years and the availability of consensus criteria for clinical diagnosis, the diagnostic accuracy of MSA remains sub-optimal. As other diagnostic tools emerge, including skin biopsy, retinal biomarkers, blood and cerebrospinal fluid biomarkers, and advanced genetic testing, a more accurate and earlier recognition of MSA should be possible, even in the prodromal stages. This has important implications as misdiagnosis can result in inappropriate treatment, patient and family distress, and erroneous eligibility for clinical trials of disease-modifying drugs.

When cerebral blood flow falls below a critical limit, syncope occurs and, if prolonged, ischemia leads to neuronal death. The cerebral circulation has its own complex finely tuned autoregulatory mechanisms to ensure blood supply to the brain can meet the high metabolic demands of the underlying neuronal tissue. This involves the interplay between myogenic and metabolic mechanisms, input from noradrenergic and cholinergic neurons, and the release of vasoactive substrates, including adenosine from astrocytes and nitric oxide from the endothelium. Transcranial Doppler (TCD) is a non-invasive technique that provides real-time measurements of cerebral blood flow velocity. TCD can be very useful in the work-up of a patient with recurrent syncope. Cerebral autoregulatory mechanisms help defend the brain against hypoperfusion when perfusion pressure falls on standing. Syncope occurs when hypotension is severe, and susceptibility increases with hyperventilation, hypocapnia, and cerebral vasoconstriction. Here we review clinical standards for the acquisition and analysis of TCD signals in the autonomic laboratory and the multiple methods available to assess cerebral autoregulation. We also describe the control of cerebral blood flow in autonomic disorders and functional syndromes.

OBJECTIVE:To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy - caused by a mutation in the IKBKAP gene (c.2204 + 6 T>C) - and characterized by marked gait ataxia. METHODS:Cervical and vestibular evoked myogenic potentials (cVEMPs and oVEMPs) were recorded from the sternocleidomastoid (SCM) and extraocular muscles in 14 homozygous patients, 2 heterozygous patients, and 15 healthy controls during percussion of the forehead. RESULTS:cVEMP and oVEMP amplitudes were significantly lower, and peak latencies significantly delayed, in the FD patients. There were no differences in overall EMG during attempted maximal voluntary contractions of the SCM muscle, suggesting intact efferent function. The two heterozygotes with a minor haplotype missense (R696P) mutation in exon 19 of the IKBKAP gene had cVEMP responses less affected than the homozygous. CONCLUSIONS:The founder mutation in the IKBKAP gene affects the development of vestibular afferent pathways, leading to attenuated cVEMPs. SIGNIFICANCE/CONCLUSIONS:Vestibular abnormalities may contribute to the gait ataxia in FD.

Our genome encodes for all proteins in the body and controls our biological functions. Mutations in DNA sequences that encode for proteins highly expressed in nerve tissue can result in specific lesions within the autonomic pathways. Mutations that result in a deficiency in a protein important for the survival of autonomic neurons at key developmental stages are usually expressed at birth or in early childhood. Hereditary sensory and autonomic neuropathies (HSAN) are a group of inherited diseases with insensitivity to pain. There are currently 6 major HSAN subtypes and at least 12 known gene-causing mutations. The severity of autonomic involvement is most profound in types 3 and 4, which are both autosomal recessive, but their autonomic phenotypes are distinctly different. Genetic mutations that result in the overexpression of proteins expressed in autonomic neurons typically present later in life and follow a more degenerative course. Familial amyloid polyneuropathies are a group of disorders caused by deposits of amyloid fibrils, most commonly due to mutations within the transthyretin (TTR) gene. This results in a length-dependent sensorimotor and autonomic neuropathy affecting unmyelinated and small myelinated fibers. The most common auto-nomic features are orthostatic hypotension, erectile dysfunction and gastrointestinal dysmotility, and can sometimes be a presenting sign. Genetic factors may also play a role in susceptibility to neurode-generative diseases. A recent genome wide association study found several genes that may emerge as genetic players in synucleinopathies including multiple system atrophy. For now, clinical trials are underway to explore whether modifying gene expression can influence the survival of autonomic neurons in HSAN3 and transthyretin-related hereditary amyloidosis. In the future, it may be possible to modify our future risk of developing an autonomic disorder with genetic therapy

Background: The arterial baroreflex buffers blood pressure to prevent it from rising or falling excessively. Afferent baroreflex failure occurs in patients with genetic or acquired lesions of the afferent (sensory) baroreceptor nerves relaying information to the brain or within the central connections of the medulla. Patients with afferent baroreflex failure have extremely volatile high and quite low pressures. Review of the literature reveals that acquired forms of afferent baroreflex failure have never been described in children or young adults. Aim: To define the cause, clinical spectrum, and treatment of acquired baroreflex failure in children and young adults. Methods: We prospectively studied consecutive pediatric and young adult patients (<30 years old) who were diagnosed with afferent baroreflex failure. Each patient underwent a detailed clinical history, neurological examination, autonomic testing, plasma catecholamine measurements, and ambulatory blood pressure monitoring. Results: We identified 6 patients (3 males and 3 females; age range: 11-28 years old). All presented with severe, labile hypotension with syncope and hypertension often accompanied by headache, and flushing. Office blood pressure ranged from a maximum of 198/138 to 143/90 mmHg and a minimum of 70/40 to 102/68 mmHg. Plasma norepinephrine levels failed to increase appropriately during head-up. On ambulatory monitoring, 24-h systolic blood pressure standard deviation was markedly exaggerated (from 17.5 to 20.8 mmHg). In all cases, patients had excessive pressor and tachycardic responses to cognitive arousal (mental-arithmetic). The underlying causes of the afferent baroreflex failure included surgery and radiotherapy of head or neck cancer (n = 4), posterior reversible leukoencephalopathy (n = 1), and Moebius syndrome (n = 1). Conclusions: Acquired afferent baroreflex failure should be considered in children and young adults with otherwise unexplained labile hypertension, particularly in those with a history of head or neck cancer

Background: Reduced pain and temperature sensation with varying degrees of autonomic dysfunction are characteristic features of patients with hereditary sensory and autonomic neuropathies (HSAN). At least seven HSAN phenotypes have been described for which 14 gene mutations have been identified. In many patients presenting with congenital sensory and autonomic deficits, however, traditional genetic testing is unable to detect genetic mutations. Objective: To identify novel genetic causes of congenital impaired sensation to pain with autonomic dysfunction with whole exome sequencing and evaluate genotype-phenotype correlations. Methods: We enrolled 10 patients with impaired or absent sensation to pain and temperature sensation with onset at birth without a previously identified molecular diagnosis from a HSAN gene panel. We performed detailed phenotypic assessment including presentation, autonomic testing, and comprehensive neurological and ophthalmo-logical examinations. Whole exome sequencing was performed in all patients as well as in, at least, one family member. Results: In 9 of 10 (90%) patients with congenital impaired pain sensation, we identified variants predicted to be pathogenic in NGF (n = 2, siblings), SMPDL3A (n = 2, siblings), SCN11A (n = 1), SCN10A (n = 1), SCN9A (n = 1), LIFR (n = 1), and TECPR2 (n = 1). Only in one patient, whole exome sequencing was not useful to identify potential pathogenic variants. Autonomic deficits included anhidrosis (SCN9A, NGF), hypohidrosis (TECPR2), hyperhidrosis (SCN11A, SCN10A, TECPR2, LIFR), alacrima or hypolacrima (SMPDL3A, TECPR2, LIFR), neurogenic dysphagia (TECPR2, SMPDL3A, SCN11A), gastroesophageal reflux (SCN11A), vomiting episodes (LIFR), and central sleep apnea (TECPR2). The subject with LIFR had episodes of hypertension, tachycardia, severe hyperhidrosis and hypernatremia. Sensorineural hearing loss was present in TECPR2 and one of the subjects with SMPDL3A. Conclusions: We characterize and expand the genetic landscape of HSAN, and demonstrate the feasibility of genetic diagnosis with clinically whole exome sequencing in 90% of our cohort